The transport of various compounds such as endogenous species, metabolites, drugs and nutrients across body such as the skin or mucosal tissue is primarily a function of three factors: tissue permeability, the presence, absence, and magnitude of a driving force, and the size of the area through which transport occurs. Body tissues such as skin and mucosal tissue are generally not sufficiently permeable to allow passive transport of molecules therethrough. That is, the permeability of many tissues is low because membranes are composed of cells and intercellular matrices that are relatively impermeable to ionized and uncharged polar species. Thus, it is the cells of the stratum corneum that present the primary barrier to absorption of topical compositions or transdermally administered drugs. The stratum corneum is a thin layer of dense, highly keratinized cells approximately 10–15 microns thick over most of the body. It is believed to be the high degree of keratinization within these cells as well as their dense packing that creates, in most cases, a substantially impermeable barrier to drug penetration. With many drugs, the rate of permeation through the skin is extremely low without the use of some means to enhance the permeability of the skin.
Iontophoresis is one approach that can be utilized to transport compounds of interest across a body tissue by the application of an electrical current. In practice, iontophoretic methods may involve positioning an electrode containing some type of drug reservoir or, in another modality of use, a collection chamber (e.g., an absorbent pad) on a body tissue, typically the skin or mucosa. A second distal electrode is placed in contact with the body tissue to complete the electrical circuit. The second electrode may also have delivery or sensing capabilities built in.
The problem with most iontophoretic devices, including constant current and constant conductance systems, is the substantial amount of energy required to achieve and maintain a target state of electroporation and transport rate. Iontophoresis can cause irritation, sensitization and pain in some patients, and the degree of irritation, sensitization and/or pain is, as a general rule, directly proportional to the applied current or voltage. For example, Dalziel and Massoglia showed a correlation between current intensity and the percentage of test subjects reporting perception of the current for both direct current (DC) and alternating current (AC). (Dalziel and Massoglia (1956) AIEE Trans. 75:49–56). Algom, Raphaeli, and Cohen-Raz found that pain perception increased as an exponential power function of the electrical current intensity. (Algom D, Raphaeli N, and Cohen-Raz L. Percept Mot Skills, Volume 65, Year 1987, Pages 619–25). Anigbogu et al. (Anigbogu et al. (2000) Int. J. Pharm. 200:195–206) showed that irritation in rabbit skin, as measured by erythema, transepidermal water loss and laser Doppler velocimetry, was directly related to the intensity of the applied electrical current.
The effects of the electrical current on sensitization have been investigated, resulting in attempts to develop iontophoretic devices and methods that are capable of maintaining the electrical current and/or potential at a comfortable level. For example, U.S. Pat. No. 5,246,418 to Haynes et al. discloses a method of reducing irritation during iontophoresis using a feedback circuit, which, during iontophoretic transport, enables control over the applied current and voltage.
A majority of the known iontophoretic methods utilize constant-current DC signals to effectuate transport. There are several problems associated with such methods that have resulted in limited acceptance by clinicians, patients and government regulators. One shortcoming of constant-current DC is that the rate of drug delivery changes with the passage of time, even though a constant current is applied. The inability to provide a constant flux at constant current is possibly due to time-dependent changes in tissue porosity, accompanying changes in pore surface charge density and effective pore size over the course of treatment. Such changes pose significant problems in effectively controlling the transdermal delivery of drugs by iontophoresis. It is generally observed that with constant-current DC methods the transference number (fraction of total current carried by a particular charged species) for the transported compound increases with time over the course of a typical iontophoresis procedure. This variability in transference number means that the amount of a compound of interest that is transported across a tissue varies with time and cannot be controlled or predicted effectively.
Problems in controlling the extent of electroporation with constant-current DC methods results in high inter-and intra-patient variability. Hence, not only does the amount of a compound transported vary as a function of time, there is further day-to-day variation for the same individual, as well as variation from person to person.
In an effort to overcome the limitations with constant current DC methods, methods that utilize AC current, either alone or in conjunction with a DC offset have been developed. Such methods are disclosed in copending U.S. application Ser. No. 09/783,138, entitled “Methods for Delivering Agents Using Alternating Current,” filed Feb. 13, 2001, corresponding to International Patent Publication No. WO 01/60449, and in U.S. application Ser. No. 09/783,696, entitled “Methods for Extracting Substances Using Alternating Current,” filed Feb. 13, 2001, corresponding to International Patent Publication No. WO 01/60448.
It has now been discovered that application of a barrier-modifying agent (also referred to herein as a “barrier-modifying agent” or “barrier modifier”) to the body tissue, either prior to or during AC iontophoresis, lowers the potential voltage difference needed to achieve electroporation. As a result, the rate at which a compound of interest can be transported through the body tissue can be maintained using lower electrical voltage levels. This reduction in applied voltage ultimately results in increased battery life, extended treatment times, decreased treatment costs, and increases patient comfort.